PB2014: A PHASE 2/3 TRIAL OF ORAL AZACITIDINE IN PATIENTS WITH LOW- OR INTERMEDIATE-RISK MYELODYSPLASTIC SYNDROMES
Authors: Guillermo Garcia-Manero, Valeria Santini, Pierre Fenaux, Takahiro Suzuki, Mikkael Sekeres, Jun He, Ronit Barkalifa, Carlos Vigil, Thomas Prebet, Rami S. Komrokji, Aristoteles Giagounidis
Journal: HemaSphere (2023)

Topic: 10. Myelodysplastic syndromes - Clinical Background: Myelodysplastic syndrome (MDS), a heterogeneous group of clonal myeloid malignancies, are characterized by ineffective hematopoiesis and peripheral blood cytopenias, which can often lead to red blood cell (RBC) transfusion dependence and a risk of progression to acute myeloid leukemia (AML). In early clinical trials, 14- and 21-day (d) dosing regimens of the hypomethylating agent oral azacitidine (Oral-AZA) were well tolerated and induced hematologic improvement (HI) in patients with lower-risk (LR) MDS. In a Phase 3 trial, Oral-AZA 300 mg QD for 21d per 28d cycle significantly improved the rate of RBC transfusion independence (TI) and induced durable HI versus placebo (PBO) in patients with LR-MDS with RBC-transfusion-dependent anemia and thrombocytopenia (Garcia-Manero, et al. J Clin Oncol 2021), although grade 3/4 cytopenias were common in the Oral-AZA arm. Taken together, these findings support further evaluation of Oral-AZA in MDS. Aims: This Phase 2/3 trial will evaluate the safety and efficacy of the 14d Oral-AZA regimen in patients with International Prognostic Scoring System Revised (IPSS-R)-defined low or intermediate (int)-risk MDS. Methods: This is an ongoing, multicenter, randomized, Phase 2/3 trial (CA055-026; NCT05469737) evaluating the effects of Oral-AZA in patients with IPSS-R low- or int-risk MDS (Figure). Key eligibility criteria include ≥ 18 years, ECOG performance status score ≤ 2, and ≥ 1 cytopenia (anemia, thrombocytopenia, or neutropenia). Patients with an absolute neutrophil count < 0.5 × 109/L within a week of randomization will be excluded. Informed consent will be obtained from all participants. The Phase 2 portion will enroll and randomize ~42 patients 1:1 to receive open-label Oral-AZA 200 or 300 mg QD for 14d per 28d cycle, plus best supportive care (BSC), to determine the recommended Phase 3 dose (RP3D). The primary endpoints are safety and rate of complete remission (CR) within 6 treatment cycles. The secondary endpoints are overall response rate (ORR), and packed (p) RBC-TI and platelet-TI sustained for 84d in ≤ 6 treatment cycles. ORR includes CR, partial remission (PR), marrow CR, and any HI, per IWG 2006 response criteria. In the Phase 3 portion, ~188 additional patients will be enrolled and randomized 1:1 to Oral-AZA at the RP3D or PBO for 14d per 28d cycle, plus BSC. Patients in the PBO arm with stable disease at treatment cycle 6 disease assessment or with documented disease progression after ≥ 3 treatment cycles will have the option to cross over into the Oral-AZA arm. The primary endpoint is CR in ≤ 6 treatment cycles. The key secondary endpoint is 84d pRBC-TI. Other secondary endpoints include those described in the Phase 2 portion plus overall survival, event-free survival, time to AML progression, iron parameters, health-related quality of life, healthcare resource utilization, and safety parameters. Patients who benefit from Oral-AZA in Phase 2 or 3 may continue to receive treatment in an extension Phase. Results:Summary/Conclusion: Trial recruitment began in December 2022 and is ongoing. Figure. Study design, key eligibility criteria, and key endpoints© 2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting. All rights reserved. Keywords: Myelodysplastic syndrome, Myeloid malignancies, Clinical trial, Hypomethylating agents